Abstract:

Background, aims and general organization.Transthyretin-related amyloidosis (ATTR) is a rare, underdiagnosed, fatal systemic condition with two main forms: hereditary ATTR (previously referred to as familial amyloid polyneuropathy, FAP; MIM 105210) and wild-type (wt) ATTR (also referred to as senile systemic amyloidosis (SSA) or senile cardiac amyloidosis, SCA). Patients with ATTR present with cardiac, polyneuropathic or mixed phenotypes, that can be influenced by genotype, geographic region and other poorly understood factors.THAOS, the TranstHyretin Amyloidosis Outcome Survey, was established in 2007 and is a worldwide, longitudinal, observational survey created to study differences in disease presentation, diagnosis, and natural history in geographically dispersed patient populations and to evaluate efficacy and safety of treatment modalities. The registry is sponsored by Pfizer Inc. and is overseen by a Scientific Board-consisting of members recruited among the participating investigators that decides on analysis of the data and publications.Symptomatic individuals with confirmed wt or variant ATTR and asymptomatic carriers of variant TTR are eligible for enrolment. Data collected include cardiac and neurologic findings, renal function assessments, quality of life assessments, hospitalizations, medications, and transplant history.

Main Results.As of June 2012, 1366 individuals from 47 sites in 19 countries had been enrolled in THAOS. The largest patient groups came from Portugal, USA, Italy, France, Brazil and Japan. Of the 1219 subjects with already validated data, 108 (104 males, 4 females) had WT ATTR and 1116 (553 males, 563 females) variant ATTR (776 symptomatic patients and 335 asymptomatic carriers). 51 different TTR mutations were identified and 9 were shared by 10 or more subjects. Val30Met was the most frequent one (75%) followed byVal122Ile ( 4.4%) and Gln89Glu (2.1%). The mutations’ distribution was highly different considering Portugal/Sweden/Japan (endemic aggregation of V30M) or USA or continental western Europe. Clinical phenotype at presentation in symptomatic patients was “mainly neurologic” in 385 (49,7%), “mainly cardiac” in 198 (25.5%) and “mixed” in 193 (24.8%). Four different mutations (Val122Ile n=49, Leu111Met n=17, Thr60Ala n=16, Ile68Leu n=17) and wt ATTR (n = 108) were associated with a cardiac phenotype at presentation characterized by symmetric left ventricular hypertrophy (LVH), normal diastolic LV volume, mildly depressed LVEF, male gender and age > 60. Age at disease onset was highly influenced by gender of the patient, gender of the transmitting parent, type of mutation and (for V30M) by geographic area. Among the 227 symptomatic patients with available echocardiographic details, both gender and age were independent predictors of LV wall thickness; only age predicted LV wall thickness in patients with “cardiac” TTR mutations and those with V30M mutations.

In conclusion,THAOS registry offers a unique opportunity to assess the phenotypic and genotypic spectrum and correlations in ATTR and can represent a model for the study of rare disease with worldwide impact. Both genotype and phenotype are highly heterogeneous. Phenotypic heterogeneity is not only linked to genotype, but also to geographic distribution, age, gender of the patient and of the transmitting parent. A clinically relevant subset of ATTRm patients (mainly associated with four different mutations) and all ATTRwt have a dominant cardiac phenotype at presentation mimicking hypertrophic cardiomyopathy. Symmetric LVH and mildly depressed LVEF especially in elderly men should prompt the suspicion of ATTR among patients with apparently unexplained left ventricular hypertrophy. THAOS registry will hopefully facilitate comprehension of the natural history of the disease and offer the potential to evaluate novel therapeutic modalities in diverse patient subpopulations.

Report:

Background.Cardiac amyloidoisis of transthyretin fibril protein (ATTR) is an infiltrative cardiomyopathy characterized by left ventricular hypertrophy (LVH) and diastolic heart failure. One subtype of ATTR is a nonhereditary form of cardiac amyloidosis in elderly men with wild type transtyretin (wt ATTR). The second subtype is a hereditary form of amyloidosis (hereditary ATTR) including variable neurological and cardiac involvement. ATTR remains a challenging and widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to a strictly cardiac presentation. The natural history of ATTR and determinants of the onset / evolution are poorly understood.

The registry and the main findings.THAOS, the TranstHyretin Amyloidosis Outcome Survey, is a worldwide observational survey created to study disease presentation, diagnosis, and natural history. This is the largest collection of patients reported so far: 1219 subjects with validated data (108 patients with WT ATTR & 1111 with hereditary ATTR). The three main results are as following:- The authors were able to detail the spectrum of mutations of TTR gene, and the relations with the geographic origin and the phenotype. Fifty-one mutations are reported, 9 are predominant, Val30Met is the most frequent one (75%), 4 mutations are associated with exclusive/main cardiac phenotype (Val122Ile, Leu111Met, Thr60Ala, Ile68Leu).- Features suggestive of hereditary ATTR are: symmetric LVH, normal diastolic LV volume, mildly depressed LVEF, male gender and age > 60 years.- Determinant of age at onset are: gender of the patient, gender of the transmitting parent, type of mutation and (for V30M) by geographic area.

Potential weaknesses and limitations can be suggested.- The design of the registry and modality of data analyses are always crucial points that may result in various bias (selection bias, measurement bias, missing information, information bias). This information is welcome to determine whether results may be affected by such limitations. Of note, the study was funded by pharmaceutical industry (Pfizer). However data were analyzed by an independent scientific board. - The analysis of features suggestive of hereditary ATTR is based on a limited population (<100 patients?) and there is a lack of comparison. We suggest to clarify the population and to make comparison with AL amyloidosis, wt ATTR and sarcomeric hypertrophic cardiomyopathy. - Determinants of age at onset are reported through univariate analyses only. Multivariate analyses are welcome.- Statistical analyses could better try to handle the complexity of the disease and take into account the potential impact on phenotype of the specific mutations and also the respective « weight » of families (large/small) since patients are not independent (index and relatives are included).- The current presentation does not report data on severity/complications at baseline and on prognosis (no follow-up data). Additional analyses are probably pending.

In conclusion,preliminary results of THAOS registry are very promising. This registry will facilitate comprehension of the natural history of the disease and its determinants. The perspective is to offer the potential to evaluate novel therapeutic modalities that are under development in ATTR (some studies are underway in ATTR patients with neurologic manifestations and other will start very soon in patients with a cardiac phenotype).